NM_001098512.3:c.13G>A

Variant names:

• chr10-50991391-G-A
• rs200844105
• NM_001098512.3:c.13G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001098512.3(PRKG1):​c.13G>A​(p.Glu5Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,548,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E5Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRKG1 NM_001098512.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.17
• Publications: 1 publications found

Genes affected

PRKG1 (HGNC:9414): (protein kinase cGMP-dependent 1) Mammals have three different isoforms of cyclic GMP-dependent protein kinase (Ialpha, Ibeta, and II). These PRKG isoforms act as key mediators of the nitric oxide/cGMP signaling pathway and are important components of many signal transduction processes in diverse cell types. This PRKG1 gene on human chromosome 10 encodes the soluble Ialpha and Ibeta isoforms of PRKG by alternative transcript splicing. A separate gene on human chromosome 4, PRKG2, encodes the membrane-bound PRKG isoform II. The PRKG1 proteins play a central role in regulating cardiovascular and neuronal functions in addition to relaxing smooth muscle tone, preventing platelet aggregation, and modulating cell growth. This gene is most strongly expressed in all types of smooth muscle, platelets, cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. Isoforms Ialpha and Ibeta have identical cGMP-binding and catalytic domains but differ in their leucine/isoleucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity. [provided by RefSeq, Sep 2011]

PRKG1 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 8

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2980354).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098512.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	NM_001098512.3		c.13G>A	p.Glu5Lys	missense	Exon 1 of 18	NP_001091982.1	Q13976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKG1	ENST00000401604.8	TSL:5	c.13G>A	p.Glu5Lys	missense	Exon 1 of 18	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396364 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 689384

African (AFR) AF: 0.0000333 AC: 1 AN: 30058

American (AMR) AF: 0.00 AC: 0 AN: 35264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24904

East Asian (EAS) AF: 0.00 AC: 0 AN: 34566

South Asian (SAS) AF: 0.00 AC: 0 AN: 78856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079306

Other (OTH) AF: 0.0000172 AC: 1 AN: 57980

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.2
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.32
Sift	Benign	0.21	T
Sift4G	Benign	0.72	T
Polyphen		0.039	B
Vest4		0.49
MutPred		0.19		Gain of ubiquitination at E5 (P = 0.0104)
MVP		0.82
ClinPred		0.91	D
GERP RS		3.9
Varity_R		0.23
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200844105; hg19: chr10-52751151;